Type II diabetes is a medical menace that affects ˜200 million people and continues to be an increasing burden on healthcare resources worldwide with its morbidities of retinopathy, cardiovascular diseases and diabetic nephropathy1. Impaired wound repair represents one of the most significant unmet medical needs in the world today and is a major complication of diabetes, resulting in significant morbidity, lost productivity, and healthcare expenditures2. Furthermore, poor healing diabetic wound is an open portal for infections, often resulting in chronic inflammation, sepsis, dehiscence and death. Despite the enormous impact these chronic wounds have, effective therapies have been lacking. To effectively manage these problems one must understand the healing process and to create a salubrious physical and biochemical environment conducive for healing.
Normal wound healing proceeds via a continuum of events that includes the acute inflammatory, proliferative and maturation phases3,4. These events entail a complex interplay between connective tissue formation, cellular activity, and growth factor activation. All three of these physiologic processes is altered in the diabetic state5,6. Extracellular matrix (ECM) components are integral to each phase of wound healing, interacting with cells and growth factors in a dynamic reciprocal manner that eventually results in wound closure.
Chronic wounds, such as venous, diabetic or pressure ulcers, represent one of the most significant unmet medical needs in the world today and are a major complication of diabetes, resulting in significant morbidity, lost productivity, and healthcare expenditures. Diabetic foot ulceration is a significant cause of morbidity and is the most common reason for hospital admission in diabetic patients. Approximately 15% of diabetic patients will develop chronic ulcers during their lifetimes. In those who require lower-limb amputation, 70-90% will be preceded by foot ulceration2.
Diabetic wounds are characterized by an accumulation of devitalized tissue, increased/prolonged inflammation, poor wound-related angiogenesis and deficiencies in the ECM components6,7. Diabetic wounds show elevated levels of matrix metalloproteinases (MMPs), increased proteolytic degradation of ECM components, inactivation of growth factors that culminate in a corrupt ECM that cannot support healing5,8. Abnormal nitric oxide (NO) production also contributes to the pathogenesis of impaired healing. Cells such as keratinocytes, fibroblasts and macrophages display both dysfunctional expression and responses to many growth factors and cytokines. Thus, these wounds typically are non-responsive to most treatments. For these reasons, it may be most advantageous to intervene with aggressive strategies that could restore corrupt extracellular microenvironment in a diabetic wound. Wound healing strategies that replace the missing or dysfunctional ECM components may be beneficial. Ideally, such replacement should be multifaceted and interactive in nature, and closely approximate the components of normal ECM. In this aspect, the role of matricellular proteins in wound healing is of interest. Matricellular proteins can associate with the diverse protein in extracellular matrix reservoir and bridged them with their cognate cell surface receptors9-11. They are expressed temporally and spatially during wound healing and resided at the crossroads of cell-matrix communication serving as a modulator for several regulatory networks. Presumably, the regulatory pathways consist of complex networks making it difficult to design for compensatory adjustments required for wound repair. It may be most advantageous to intervene with aggressive healing strategies that replace the missing or dysfunctional extracellular matrix (ECM) components. Ideally, such replacement should be multifaceted and interactive in nature, and closely approximate the components of the normal ECM, leading to accelerated wound closure with minimal scar formation. Hence, while targeting or replacing the necessary matricellular proteins may be more efficacious than individual cytokine-mediated candidates it is difficult to know where to begin or what strategy may be successful.
To effectively manage these problems one must understand the healing process and to create a salubrious physical and biochemical environment conducive for healing. These non-healing wounds have been the subject of intensive investigation throughout the past 15 years. Much effort has focussed on recombinant growth factors. Given that the targets of members of the epidermal growth factor, fibroblast growth factor, platelet-derived growth factor (PDGF), and transforming growth factor-ß families were cells that participated in the dermal wound repair process, it was logical to use this model as the first foray into clinical studies with these growth factors. With one notable exception (PDGF-BB or becaplermin), this drug development effort may be considered a failure for several reasons (Pierce & Mustoe 1995), among the most significant reason was that these growth factors typically target a single biological process essential for wound healing. To date, the only growth factor approved by the US Food and Drug Administration for the treatment of diabetic foot ulcers is recombinant PDGF-BB (becaplermin), which comes in as a topical cream. PDGF-B is known to be a potent mitogen and chemotatic agent for stromal cells and may act to increase the wound vascularization by stimulating angiogenesis. Thus there is an urgent need for better, new or adjunctive treatments.
Angiopoietin-like protein 4 (ANGPTL4) are secreted proteins mainly expressed in liver that have been demonstrated to regulate triglyceride metabolism by inhibiting the lipolysis of triglyceride-rich lipoproteins. Experimental results show that ANGPTL4 function to regulate circulating triglyceride levels during different nutritional states and therefore play a role in lipid metabolism during feeding/fasting through differential inhibition of Lipoprotein lipase (LPL). The N-terminal domain of Angiopoietin-like proteins has been shown to play an active role in lipid metabolism. Using deletion mutants, it was demonstrated that the N-terminal domain containing fragment—(17-207) and not the C-terminal fibrinogen-like domain containing fragment—(207-460) increased the plasma triglyceride levels in mice: ANGPTL4 has been identified as a novel paracrine and, possibly, endocrine regulator of lipid metabolism and a target of peroxisome proliferators-activated receptors (PPARs). It is expressed in numerous cell types, such as adipocytes and hepatocytes, and is upregulated after fasting and hypoxia. Importantly, ANGPTL4 undergoes proteolytic processing to release its C-terminal fibrinogen-like domain (cANGPTL4), which circulates as a monomer yet whose function remains unclear. The N-terminal coiled-coil domain of ANGPTL4 (nANGPTL4) mediates the oligomerization of ANGPTL4 and binds to lipoprotein lipase to modulate lipoprotein metabolism mediating oligomerization and lipoprotein metabolism. In contrast, cANGPTL4 exists as a monomer, and its function still remains unknown. ANGPTL4 has been showed to play a context-dependent role in angiogenesis and vascular permeability13-15. ANGPTL4, was a recently identified to be a matricellular protein implicated in regulation of energy metabolism and wound healing12. The deficiency in ANGPTL4 in mice (ANGPTL4−/−) resulted in delayed wound re-epithelialization, reduced matrix proteins expression, an increased inflammation and an impaired wound-related angiogenesis16,17. However, the expression of ANGPTL4 and role in chronic wound repair, such as diabetic wound repair remains unclear.